ES2671732T3 - Improved procedure for preparing an intermediate compound of the TMC 435 macrocyclic protease inhibitor - Google Patents

Abstract

A process for preparing a compound according to the following scheme **Formula ** wherein: n is 0-8; Rx represents hydrogen; G represents -ORx1 or -N(H)SO2Rx2; Rx1 represents hydrogen or C1-6 alkyl; Rx2 represents C1-6 alkyl or C3-6 cycloalkyl; X represents N or CH; Y represents N or CH; when Y represents N, then Y1 represents hydrogen or C1-6 alkyl; when Y represents CH, then Y1 represents -C(O)-Rx3, -S(O)1-2-Rx3, -C(S)-Rx3, -N(Rx3)-Rx4, -N(H)-C (O)-ORx3 or -N(H)-C(O)-Rx4; Rx3 and Rx4 represent, independently, C1-6 alkyl, C3-6 cycloalkyl, aryl or heteroaryl (the latter two groups of which are optionally substituted with one or more substituents selected from halo and C1-6 alkyl); L represents -O- or -OC(O)-; Ry represents aryl, heteroaryl or cyclic non-aromatic group, all of which are optionally substituted with one or more substituents, characterized by the steps of a) acylating the first compound (in Rx) with a halogenated acyl compound (R2-CO )2O or R2-COCl, where R2 is polyhaloC1-4alkyl, followed by a ring-closing metathesis reaction of the acylated reaction product with a suitable catalyst in a reaction-inert solvent to provide a compound; and b) separating the halogenated acyl group from the compound obtained in (a) above, thus obtaining the final compound.

Description

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1. A procedure for preparing a compound according to the following scheme

image 1

n is 0-8;

Rx represents hydrogen;

G represents -ORx1 or -N (H) SO2Rx2;

Rx1 represents hydrogen or C1-6 alkyl;

Rx2 represents C1-6 alkyl or C3-6 cycloalkyl;

X represents N or CH;

Y represents N or CH;

when Y represents N, then Y1 represents hydrogen or C1-6 alkyl;

when Y represents CH, then Y1 represents -C (O) -Rx3, -S (O) 1-2-Rx3, -C (S) -Rx3, -N (Rx3) -Rx4, -N (H) -C (O) -ORx3 or -N (H) -C (O) -Rx4;

Rx3 and Rx4 independently represent C1-6 alkyl, C3-6 cycloalkyl, aryl or heteroaryl (whose last two groups are optionally substituted with one or more substituents selected from halo and C1-6 alkyl);

L represents -O- or -OC (O) -;

Ry represents aryl, heteroaryl or cyclic non-aromatic group, all of which are optionally substituted with one or more substituents,

which is characterized by the stages of

a) acylating the first compound (in Rx) with a halogenated acyl compound (R2-CO) 2O or R2-COCl, wherein R2 is C1-4 polyhaloalkyl, followed by a metathesis reaction with ring closure of the reaction product acylated with a suitable catalyst in a reaction inert solvent to provide a compound; Y

b) separating the halogenated acyl group from the compound obtained in (a) above, thus obtaining the final compound.

2. A process according to claim 1 for preparing a compound of formula (II), wherein R1 is C1-6 alkyl,

image2

which is characterized by the stages of

a) acylating a diene compound of formula (I), wherein R 1 is C 1-6 alkyl,

5

image3

with a halogenated acyl compound (R2-CO) 2O or R2-COCl, wherein R2 is C1-4 polyhaloalkyl, followed by a ring metathesis reaction of the acylated reaction product with a suitable catalyst in an inert solvent to the reaction to provide a compound of formula (III); Y

image4

10 b) separating the halogenated acyl group from the compound (III), thus obtaining the compound of formula (II), wherein R 1 is C 1-6 alkyl.

image5

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3. The process according to claim 2, wherein R1 represents C1-4 alkyl.

4. The process according to claim 3, wherein R1 represents ethyl.

5. The process according to any one of claims 1 to 4, wherein the halogenated acyl compound is (R2-CO) 2O.

6. The process according to claim 5, wherein R2 represents trifluoromethyl, chloro-difluoromethyl or heptafluoropropyl.

7. The process according to claim 6, wherein R2 represents chlorodifluoromethyl.

8. The process according to any one of claims 1 to 7, wherein the suitable catalyst in the metathesis reaction with ring closure is selected from [1,3-bis (2,4,6-trimethylphenyl) - 2- imidazolidinylidene] dichloro (phenylmethylene) (tricyclohexylphosphine) ruthenium, [1,3-bis (2,4,6-trimethylphenyl) -2-

imidazolidinylidene] dichloro [[2- (1-methylethoxy-KO) phenyl] methylene-KC], dichloro (3-phenyl-1H-inden-1-

ilidene) bis (tricyclohexylphosphine) ruthenium or bis (tricyclohexyl phosphine) [(phenylthio) methylene] ruthenium dichloride,

dichloro (phenylmethylene) bis (tricyclohexylphosphine) ruthenium, dichloro [[2- (1-methylethoxy-a-O) phenyl] methylene-a-

C] (tricyclohexylphosphine) ruthenium, [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro (3-phenyl-7H-inden-1-ylidene)

(tricyclohexylphosphine) ruthenium, [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro (3-phenyl-1H-inden-1-

ilidene) (triphenylphosphine) ruthenium and [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro [[4 - [(dimethylamino) sulfonyl] -2- (1- methylethoxy-KO) phenyl] methyl-KC] ruthenium.

9. The method according to claim 8, wherein the suitable catalyst in the metathesis reaction

with ring closure is [1,3-bis (2,4,6-trimethylphenyl) -2-imidazolidinylidene] dichloro (3-phenyl-1H-inden-1-

ilidene) (tricyclohexylphosphine) ruthenium.

10. The process according to any one of claims 1 to 9, wherein the metathesis reaction with ring closure is carried out in the presence of soluble tetraalkylammonium iodide in a reaction solvent, selected from tetramethylammonium iodide ( TMAI), tetraethylammonium iodide (TEAI), tetrapropylammonium iodide (TPAI) or tetrabutylammonium iodide (TBAI).

11. The process according to any one of claims 1 to 10, wherein the separation of the halogenated acyl group (eg, of the compound (NI)) is carried out by treatment with a secondary amine, in particular dimethylamine

12. The process according to any one of claims 1 to 11, wherein steps a) and b) are carried out in a reaction in a single vessel.

13. A compound of formula (III)

image6

14. The compound according to claim 13, wherein R1 represents ethyl and R2 represents trifluoromethyl, chlorodifluoromethyl or heptafluoropropyl.

15. Use of tetraalkylammonium iodides soluble in a reaction solvent to increase the reaction rate and yield in a ring closure metathesis reaction according to any one of claims 1-9, carried out in an ilidene-based catalyst. Ru.

16. The use according to claim 15, wherein the tetraalkylammonium iodides are selected from tetramethylammonium iodide (TMAI), tetraethylammonium iodide (TEAI), tetrapropylammonium iodide (TPAI) or iodide of

tetrabutylammonium (TBAI).

17. A compound of the formula:

image7

wherein Rx represents -C (O) R2, and the remaining integers are defined in claims 1 and 2. 10 18. A process for the preparation of TMC435:

image8

process comprising the conversion of a compound of formula (II), as defined in claim 2, into TMC435, wherein the compound of formula (II) is prepared according to a process according to any one of claims 2 to 12.

15. A process for the preparation of a pharmaceutical composition comprising TMC435, process

which comprises a process for the preparation of TMC435 according to claim 18, followed by contacting the product with a pharmaceutically acceptable carrier, diluent and / or excipient.

Claims (1)

5 10 fifteen twenty 25 30 35 40 Four. Five fifty 55 60 65 DESCRIPTION Procedure of treatment of hot flashes associated with carcinoid tumors and carcinoid syndrome CROSSED REFERENCE TO RELATED PATENT APPLICATIONS This application claims priority over the provisional US request. Serial No. 62 / 019,067 filed June 30, 2014. BACKGROUND OF THE PRESENT INVENTION Carcinoid tumors are rare cancerous tumors that generally affect the gastrointestinal tract or lungs. Tumors sometimes lead to the secretion of chemicals in the bloodstream, causing various symptoms collectively called carcinoid syndrome. From about 5% to about 10% of patients with carcinoid tumors have the symptoms of carcinoid syndrome. The most common symptom of carcinoid syndrome is redness of the face, neck and / or upper chest. The blush includes changes in color, usually redness, of the affected areas and, sometimes, sensations of heat. New therapies are needed to treat the blush associated with carcinoid tumors and carcinoid syndrome in order to improve the quality of life of patients with carcinoid tumors and carcinoid syndrome. US 2012/0101141 A1 discloses topical gel compositions comprising an alpha adrenergic receptor agonist selected from the group consisting of oxymetazoline, phenylephrine, methoxamine, tetrahydrozoline, nafazoline, xylometazoline, epinephrine and norepinephrine for the treatment of disorders of the skin. The following skin disorders are mentioned: rosacea, telangiectasia, psoriasis, purpura, acne erythema, eczema, inflammation of the skin not related to rosacea, flushing, sagging, creasing and / or wrinkles. US 2006/0264515 A1 discloses topical formulations comprising an alpha adrenergic receptor agonist for the treatment of telangiectasias. WO 2011/053487 A1 discloses a method for treating or preventing acute erythema by topically administering an effective amount of an alpha adrenergic receptor agonist or a pharmaceutically acceptable salt thereof. CHARACTERISTICS OF THE PRESENT INVENTION The present invention relates to a pharmaceutical composition for use in the treatment of blush associated with carcinoid tumors and carcinoid syndrome in a patient in need thereof, a composition comprising an alpha adrenergic receptor agonist, a pharmaceutically acceptable salt thereof or combinations. Of the same; and to a pharmaceutically acceptable carrier, in which the composition is to be applied topically at the blush site. In one embodiment, the site of the blush is the face or neck. Preferably, the alpha adrenergic receptor agonist is an alpha-1 adrenergic receptor agonist or an alpha-2 adrenergic receptor agonist. The alpha-1 adrenergic receptor agonist or the preferred alpha-2 adrenergic receptor agonist is brimonidine, tetrahydrozoline, nafazolin, xylometazoline, epinephrine, norepinephrine, oxymetazoline, phenylephrine or methoxamine. The most preferred alpha-2 adrenergic receptor agonist is brimonidine or a pharmaceutically acceptable salt thereof. Brimonidine or a pharmaceutically acceptable salt thereof is preferably present in an amount of about 0.5% by weight to about 5% by weight of the composition, more preferably about 0.5% by weight at approximately 2% by weight of the composition. In a preferred embodiment, brimonidine or its pharmaceutically acceptable salt thereof is present in an amount of approximately 0.33% by weight of the composition. Preferably, the pharmaceutically acceptable carrier is a gel, cream, ointment, lotion or emulsion. Gels are preferred vehicles. DETAILED DESCRIPTION The present invention relates to the pharmaceutical composition mentioned above for use in the treatment of blush associated with carcinoid tumors and carcinoid syndrome in a patient in need. Carcinoid syndrome is a pattern of symptoms that is observed in approximately 5% to approximately 10% of patients with carcinoid tumors. The most common symptom of carcinoid syndrome is flushing of the face, neck and / or upper chest. The blush affects the skin of the face, neck and / or upper chest, which change color from pink to red to purple and, sometimes, sensations of heat. Redness of the skin is most often associated with flushing. Blush episodes can last from a few minutes to a few hours or more. A pharmaceutical composition for use in the treatment of flushing associated with carcinoid tumors and carcinoid syndrome in accordance with the present invention includes an effective amount of one or more alpha-adrenergic receptor agonists or a pharmaceutically acceptable salt thereof and a pharmaceutically vehicle. acceptable, in which the composition will be applied topically to the skin at the site of the blush. Alpha adrenergic receptor agonists are well known in the art. In a preferred embodiment, the alpha adrenergic receptor agonist may be an alpha-1 or alpha-2 adrenergic receptor agonist. The alpha-adrenergic receptor agonists 5 included in the composition for use in accordance with the present invention may or may not show selectivity for alpha-1 or alpha-2 adrenergic receptors. For example, some may be considered alpha-1 and alpha-2 adrenergic receptor agonists. More preferably, the alpha adrenergic receptor agonist may be a selective alpha-1 adrenergic receptor agonist or alpha-2 selective. 10 Examples of selective alpha-1 adrenergic receptor agonists include oxymetazoline, phenylephrine and methoxamine. Examples of selective alpha-2 adrenergic receptor agonists include brimonidine, tetrahydrozoline, nafazolin, xylometazoline, epinephrine and norepinephrine. The chemical structures of some selective alpha-1 adrenergic receptor agonists and alpha-2 selective agonists are shown below.

 Chemical structure

 Name

 H f Cr "T¿0

 (5-Bromo-quinoxalin-6-yl) - (4,5-dihydro-1H-imidazol-2-yl) -amine (Brimonidine)

 r- \ HN N in

 Tetrahydrozoline

 JO

 Nafazolin

 today V ^!> \ ji JL hn-7

 Oxymetazoline

 1 ____. N. [| V f) \ II -1 HN— '

 Xylometazoline

 ?H H

 Epinephrine

 OH H0 ^^ k / NH2

 Norepinephrine

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 Chemical structure

 Name

 ?H H

 Phenylephrine

 OH 1

 Methoxamine

Brimonidine and its pharmaceutically acceptable salts are preferred embodiments of the composition underlying the present invention. Preferably, the active ingredient of the composition for use in accordance with the present invention is brimonidine tartrate. The alpha-1 adrenergic receptor agonist, the alpha-2 adrenergic receptor agonist, or a pharmaceutically acceptable salt thereof may be administered alone or in combination with one or more adrenergic alpha-1 receptor agonists, alpha-2 receptor agonist. adrenergic or a pharmaceutically acceptable salt thereof. For example, the active ingredients in the pharmaceutical composition may include brimonidine tartrate and oxymetazoline hydrochloride. Pharmaceutically acceptable salts for each alpha adrenergic receptor agonist are well known in the art. Pharmaceutically acceptable salt means the salts of compounds underlying the composition for use in accordance with the present invention that are safe and effective for topical use in mammals and possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds underlying the composition for use in accordance with the present invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, the hydrochloride, hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate salts, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3- naphthoate)). Certain compounds underlying the composition for use in accordance with the present invention may form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, the aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. Pharmaceutically acceptable salts are treated in BERGE AND OTHERS, 66 J. PHARM. SCI. 1-19 (1977). Pharmaceutical compositions include any formulation that is pharmaceutically acceptable for topical administration of the compounds underlying the composition for use in accordance with the present invention. The choice of topical formulation will depend on several factors, including the physicochemical characteristics of the particular compound or compounds and other excipients present, its formulation stability, available manufacturing equipment and cost limitations. The pharmaceutically acceptable composition is applied locally to the site of the affected skin of the patient in any conventional manner well known in the art. For example, the composition can be a gel that can be applied to the patient's face and neck using fingertips. The amount of agonist of the alpha adrenergic receptor applied to the skin is any amount that is effective in treating the blush associated with carcinoid tumors and carcinoid syndrome. Generally, the minimum amount of an alpha adrenergic receptor agonist in a topical formulation for use in accordance with the present invention to be applied to the affected area of the skin is approximately 0.0001 g / cm.2, preferably approximately 0.001 g / cm2 of the surface area of the skin. The maximum amount of an alpha adrenergic receptor agonist in a topical formulation for use in accordance with the present invention to be applied to the affected area of the skin is from about 0.05 g / cm.2, to about 0.008 g / cm2 of the surface area of the skin. Normally, one to four applications per day are recommended during the treatment period. Doses and dosage frequency will be determined by a medical professional trained depending on the activity of the compound underlying the composition for use in accordance with the present invention, the characteristics of the particular topical formulation and the general physical condition of the person. What is being treated. 5 10 fifteen twenty 25 30 35 40 In general, each alpha adrenergic receptor agonist or pharmaceutically acceptable salt thereof is present in a formulation for use in accordance with the present invention in a minimum amount of about 0.05 percent, about 0.1 percent or approximately 0.15 percent of the total weight of the formulation. Preferably, an alpha adrenergic receptor agonist or pharmaceutically acceptable salt thereof is present in a formulation for use in accordance with the present invention in a maximum amount of about 5 percent, about 2 percent or about 1 percent. or about 0.5 percent of the total weight of the formulation. It should be understood that the present invention contemplates embodiments in which each minimum is combined with each maximum to create all feasible intervals. For example, each alpha-adrenergic receptor agonist or pharmaceutically acceptable salt thereof may be present in a composition for use in accordance with the present invention in an amount of about 0.05 percent to about 1 percent based on total weight of the composition or, similarly, from about 0.1 percent to about 1 percent based on the total weight of the composition. The compounds of the composition for use in accordance with the present invention should be administered in the affected area of the skin in a pharmaceutically acceptable carrier. As used herein, a pharmaceutically acceptable carrier is any pharmaceutically acceptable formulation that can be applied to the skin surface for topical or dermal administration of a drug or pharmaceutical substance. The combination of a pharmaceutically acceptable carrier and a compound underlying the composition for use in accordance with the present invention is called a pharmaceutical composition for use in accordance with the present invention. Pharmaceutical compositions for use in accordance with the present invention are prepared by mixing a compound of the present invention with a topical vehicle according to procedures well known in the art, for example, procedures provided by standard reference texts, such as REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 16721673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K .; and others. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997). See also the discussion of pharmaceutical compositions containing alpha adrenergic receptor agonists in US Patent No. 7,439,241. Topical carriers useful for topical administration of compounds underlying the composition for use in accordance with the present invention may be any vehicle known in the art for topical administration of pharmaceuticals, for example, but not limited to, solvents. pharmaceutically acceptable, such as polyalcohol or water; emulsions (oil in water or water in oil emulsions), such as creams or lotions; microemulsions; gels; ointments; liposomes; powder; and aqueous solutions or suspensions. Preferred vehicles are gels, creams, ointments, lotions and emulsions. EXAMPLES Example 1 Gel composition

 Ingredient

 Weight percentage

 Brimonidine Tartrate

 0.33%

 Carbomer 934P

 1.25%

 Methylparaben

 0.3%

 Phenoxyethanol

 0.4%

 Glycerin

 5.5%

 10% titanium dioxide

 0.625%

 Propylene glycol

 5.5%

 10% NaOH solution

 6.5%

 Deionized water

 c.s.

 TOTAL

 100%

Example 2 Cream composition

 Ingredient

 Weight percentage

 Brimonidine Tartrate

 C

 Oxymetazoline Hydrochloride

 0.5%

 Phenoxyethanol

 0.8%

 Methylparaben

 0.2%

 Propylparaben

 0.05%

 Disodium EDTA

 0.01%

 Butylated Hydroxytoluene

 0.05%

 PEG -300

 4.0%

 PEG-6 stearate (y) glycolestearate (y) PEG-32 stearate

 7.5%

 Ketostearyl alcohol

 4.0%

 Caprylic / Capric Triglycerides

 7.0%

 Diisopropyl adipate

 7.0%

 Oleyl alcohol

 7.0%

 Lanolin USP

 2.0%

 Ceteareth-6 (and) stearyl alcohol

 2.0%

 Ceteareth-25

 2.0%

 Tartaric acid

 0.001%

 Deionized water

 55.389%

 TOTAL

 100%

Example 3 Lotion composition

 Ingredient

 Weight percentage

 Brimonidine Tartrate

 0.25%

 Amerlate P isopropyl lanolate

 0.5%

 Stearic acid

 3.0%

 Glyceryl stearate

 2.0%

 Methyl Gluceth-20

 5.0%

 Triethanolamine

 1.0%

 Water

 83.45%

 Polyquaternium-24 and hyaluronic acid (BIOCARE Polymer HA-24)

 3.8%

 Germaben IIE

 1.0%

 TOTAL

 100%

Example 4 A gel containing 0.33% by weight of brimonidine tartrate is administered on the face and neck of a patient with carcinoid syndrome. The patient applies the gel on their skin twice a day as needed.